Chronic hyperglycemia is believed to reduce both insulin secretion and insulin sensitivity, which in turn will cause elevation of blood glucose levels and lead to exacerbation of diabetes. Drugs conventionally used as therapeutic agents for diabetes include biguanides, sulfonylureas, glycosidase inhibitors and insulin-resistance improving agents. However, adverse side effects of these drugs have been reported; for example, lactic acidosis for biguanides, hypoglycemia for sulfonylureas, and diarrhea for glycosidase inhibitors. It is therefore desirable to develop therapeutic agents for diabetes that depend on a new mechanism of action which is different from those conventionally proposed.
Phloridzin, a glucose derivative isolated from nature, has been identified as having a hypoglycemic effect by inhibiting excessive glucose reabsorption in the kidney to accelerate the glucose excretion (J. Clin. Invest., vol. 80, p. 1037, 1987; J. Clin. Invest., vol. 87, p. 1510, 1987). There have been indications that this glucose reabsorption event is mediated by sodium-dependent glucose transporter 2 (SGLT2) present at the S1 site of renal proximal tubules (J. Clin. Invest., vol. 93, p. 397, 1994).
Under these backgrounds, an increasing number of studies have been conducted to develop therapeutic agents for diabetes that depend on SGLT2 inhibition, and a large number of phloridzin derivatives have been reported (European Patent Publication No. EP0850948, International Patent Publication Nos. WO0168660, WO0116147, WO0174834, WO0174835, WO0253573, WO0268439, WO0228872, WO0268440, WO0236602, WO0288157, WO0228872, WO0244192, WO0264606, WO0311880, WO0320737, WO0300712, etc.). When administered orally, phloridzin derivatives are hydrolyzed at glycosidic linkages by the action of glycosidase present in the small intestine, thus resulting in low absorption efficiency of unchanged form and a weak hypoglycemic effect. For this reason, various attempts have been made, for example, to increase absorption efficiency by administering phloridzin derivatives in the form of prodrugs and/or to prevent digestion by synthesizing compounds replaced by carbon-carbon linkages instead of glycosidic linkages (United States Patent Nos. US20010041674, US2002137903 and US20031143, International Patent Publication Nos. WO0127128 and WO0283066, Tetrahedron Lett., vol. 41, p. 9213, 2000).
The inventors of the present invention have focused on 5-thioaldopyranoses as glucose analogs, in which the ring oxygen atom of aldopyranose is replaced by a sulfur atom. Such 5-thioaldopyranoses will show biological and chemical properties that are different from those of aldopyranoses.
However, there is no report on β-glycosidic linkage formation between aryl and 5-thioglucose in which the ring oxygen atom of glucose is replaced by a sulfur atom. Thus, there is also no report on the SGLT-inhibiting effect of 5-thio-β-D-glucopyranoside derivatives.
With the aim of developing glycosidase inhibitors, an attempt has been made to synthesize disaccharides having a 5-thiofucopyranose group or a 5-thioglucopyranose group at their nonreducing end, and it has also been reported that the trichloroacetoimidate method is effective for glycosidic linkage formation in this attempt (Tetrahedron Lett., vol. 25, p. 212, 1993, Tetrahedron Lett., vol. 33, p. 7675, 1992). In general, it has been widely known that, if a glycosyl donor has an acyl group at the 2-position, the neighboring group participation is successfully available and predominantly leads to the formation of 1,2-trans-glycosidic linkages. Interestingly, however, it has been known that, when the same approach is used in the case of 5-thioaldopyranoses, 1,2-cis-glycosides are predominantly obtained, but 1,2-trans-glycosides are not selectively obtained (Tetrahedron Assymm., vol. 5, p. 2367, 1994, J. Org. Chem., vol. 62, p. 992, 1997, Trends in Glycoscience and Glycobiology, vol. 13, p. 31, 2001). There are only two reports previously known for selective 1,2-trans-glycoside synthesis of saccharides: synthesis of 5′-thio-N-lactosamine using glycosyltransferase and UDP-5′-thiogalactose (J. Am. Chem. Soc., vol. 114, p. 5891, 1992) and an approach using benzoyl-protected 5-thioglucopyranosyl trichloroacetoimidate (Chem. Lett., p. 626, 2002).
In addition, the Mitsunobu reaction between 4-nitrophenol and 5-thio-L-arabinopyranose can be presented as an example of 5-thioglycosidic linkage formation using phenol as a glycosyl acceptor (Carbohydr. Res., vol. 311, p. 191, 1998). Alternatively, there is also a report of the Lewis acid-catalyzed condensation between thiophenol (Tetrahedron, vol. 49, p. 8977, 1993) or phenylselenol (Tetrahedron Assymm., vol. 5, p. 2367, 1994) and 5-thio-D-glucopyranose. However, these reactions would also yield a mixture of 1,2-cis- and 1,2-trans-glycosides as their reaction product. Namely, no method is known for selective chemical synthesis of aryl 1,2-trans-5-thioglycosidic linkages (β-5-thioglycosides).